Cyclic adenosine 3′,5′-monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP) as intracellular signal transduction molecules (second messengers) are degraded by a group of hydrolases generally called phosphodiesterase (PDE) into inactive 5′-AMP and 5′-GMP, respectively.
PDE isozymes which inactivate them are not uniformly present in vivo but distributed in vivo having an organ-specific localization by showing differences, e.g., in cell distribution and tissue distribution.
Up to date, the presence of 11 families of PDE1 to PDE11 has been confirmed (see Current Opinion in Cell Biology, 12, 174-179 (2000)).
Among these PDEs, PDE4 is present in various cells such as airway smooth muscle cells, epitherial cells, inflammatory cells (macrophages, neutrophils and eosinophils) and T lymphocytes, etc. and controls cellular functions by regulating the intracellular cAMP level of these cells. On the other hand, other PDEs such as PDE5 etc. are present in, e.g., platelets, cardiac muscle cells and vascular smooth muscle cells and participate in the control of circulatory organ system by regulating intracellular cGMP or cAMP level.
Thus, it is known that PDE4 inhibitors have bronchodilatory activity, anti-inflammatory activity, mediator release inhibitory activity, immunosuppressive activity and the like, because they cause accumulation of intracellular cAMP by inhibiting degradation of cAMP by PDE4.
Accordingly, it is considered that agents which specifically inhibit PDE4 do not show the activities of other PDE inhibition such as PDE5 upon circulatory organs and are useful in preventing and/or treating various diseases such as inflammatory diseases (e.g. asthma, obstructive lung disease, sepsis, sarcoidosis, nephritis, hepatitis, enteritis, etc.), diabetic diseases, allergic diseases (e.g. allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (e.g. ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen disease, etc.), ocular diseases (e.g. allergic conjunctivitis, seasonal conjunctivitis, etc.), osteoporosis, bone fracture, osteoarthritis, obesity, bulimia, depression, Parkinson's disease, dementia, ischemia-reperfusion injury, leukemia and AIDS (Exp. Opin. Invest. Drugs, 8, 1301-1325 (1999)), shock, systemically inflammatory responsive diseases (SIRS), etc.
As PDE4 inhibitors, for example, the specification of JP Hei 8-509731 (i.e. WO94/25437) discloses that a compound of formula (A)
(wherein R1A represents H or C1-6 alkyl; R2A represents C3-7 alkyl, C3-7 cycloalkyl, etc.; R3A represents COR4A, COCOR4A, etc.; R4A represents H, OR5A, NHOH, etc.; R5A represents H, C1-6 alkyl, etc.; XA represents O etc.; and YA represents O etc.) or a pharmaceutically acceptable salt thereof has a PDE4 inhibitory activity.
Also, the specification of WO 93/19747 discloses that a compound of formula (B)
(wherein R1B represents —(CR4BR5B)rBR6B etc., rB is 1 to 6; R4B and R5B each independently represents a hydrogen atom or a C1-2 alkyl group; R6B represents a hydrogen atom, a C3-6 cycloalkyl group, etc.; XB represents YBR2B etc.; YB represents O etc.; R2B represents methyl, ethyl, etc.; X2B represents O etc.; X3B represents a hydrogen atom etc.; sB is 0 to 4; R3B represents a hydrogen atom, CN, etc.; X5B represents a hydrogen atom etc.; ZB represents CR8BR8BC(O)OR14B, CR8BR8BC(Y′B)NR10BR14B, etc.; R8B represents a hydrogen atom etc.; R10B represents a hydrogen atom, OR8B, etc.; and R14B represents a hydrogen atom etc.) or a pharmaceutically acceptable salt thereof has a PDE4 inhibitory activity.
Also, the specification of WO 93/19749 discloses that a compound of formula (C)
(wherein R1C represents —(CR4CR5C)rCR6C, etc.; rC is 1 to 6; R4C and R5C each independently represents a hydrogen atom or a C1-2 alkyl group; R6C represents a hydrogen atom, a C3-6 cycloalkyl group, etc.; XC represents YCR2C etc.; YC represents O, etc.; R2C represents methyl, ethyl, etc.; X2C represents O, etc.; X3C represents a hydrogen atom etc.; X4C represents
etc.; R3C represents a hydrogen atom, CN, etc.; X5C represents a hydrogen atom etc.; sC is 0 to 4; ZC represents C(O)OR14C, C(Y′C)NR10CR14C, etc.; R10C represents a hydrogen atom OR8C, etc.; R8C represents a hydrogen atom etc.; and R14C represents a hydrogen atom etc.) or a pharmaceutically acceptable salt thereof has a PDE4 inhibitory activity.
The present applicant previously filed a patent application about piperidine derivative of formula (D)
(wherein all symbols have the same meanings as described in PCT/JP01/06861.) and a non-toxic salt thereof and a PDE4 inhibitor comprising it as an active ingredient (see the specification of WO 02/14280). Particularly, example 2(9) in the world patent application discloses 2-(4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-4-cyanopyperidin-1-yl acetic acid of formula (E)
